Recent advances in small-angle scattering and optical anisotropy studies on ocular lens have implicated that both the aggregation and organization of crystallins into macro and/or super-molecular complexes are important in maintaining lens transparency. The aggregation mechanism has been investigated by chemical modification using native alpha-crystallin as a model. Isolation and characterization of the variously sized populations resulting from reacting specific functional groups indicate that non-covalent interactions are determining the aggregation of the native as well as subunits of alpha-crystallin. Data from the circular dichroism and sedimentation in the analytical ultracentrifuge suggest that small or localized changes in amino acid side-chain chromophore(s) can cause the aggregation of lens proteins into different sized populations. Results from solvent perturbation indicate that the distribution and formation of lens crystallins in a medium of high density similar to that prevails in vivo are different from those observed in a dilute buffer. Thermodynamic analyses suggest the involvement of both a reversible and an irreversible equilibrium between crystallins and lenticular components. These data support the hypothesis that lens proteins are organized into supermolecular aggregates in vivo. Changes in hydration and thereby the hydrophobicity of lens protein polypeptides due to environmental perturbations can disrupt these structures and cause opacification.